ABSTRACT Osteoporosis is a common skeletal degenerative disorder that is characterized by decrease of bone-mass and micro-architectural deterioration of bone tissue. It results from increased osteoclast (OC)-mediated bone resorption and/or reduced osteoblast (OB)-mediated bone formation. Alzheimer's disease (AD) is a common neurodegenerative disorder with cognitive dementia. Intriguingly, AD patients frequently have lower bone mineral density and higher rate of hip fracture, compared with the same age normal population. Several newly identified AD risk genes/loci encode proteins critical for osteoclastic activation and/or bone-mass homeostasis. Increasing evidence from clinical and genetic studies thus supports a degree of association of both disorders. However, very few studies are available to address the underlying mechanisms. The goal of this proposal is to determine if and how the Swedish mutant amyloid precursor protein (APPswe) acts as a risk factor for osteoporosis. APP is a ubiquitously expressed transmembrane protein. Its cleavage product, A?, is believed to be a major culprit for both early- and late-onset AD. We thus explored the possible contribution of APPswe to AD- associated skeletal deficits in mice. Tg2576 mice express APPswe under the control of prion promoter, and develop AD-relevant neuro-pathologic deficits at older age (>10 months old). Remarkably, our preliminary studies revealed age-dependent osteoporotic deficits in this AD animal model, including reduced trabecular bone-mass in young adult age and deteriorated bone tissue at older age. The reduced bone-mass was associated with a decrease in osteoblastic bone formation and an increase in osteoclastic bone resorption. The deteriorated bone structure was preceded by an impaired osteoclastic bone resorption. To investigate underlying mechanisms, we generated a transgenic mouse that enables cell-type specific expression of APPswe in OBs and OCs. Our results suggest that APPswe plays a cell autonomous role in suppressing OB-mediated bone formation and in regulating OC activation. These results uncovered potentially novel cellular mechanisms by which APPswe disrupts bone homeostasis. However, underlying molecular mechanisms remain unclear. In this proposal, we will address this issue. This research will not only provide a potential link between AD and skeletal deficits, but also identify unrecognized functions of APP and APPswe, and reveal new pathophysiological mechanisms underlying osteoporosis and AD, both chronic degenerative disorders affecting many veteran's quality of life and highly relevant to Strategic Objectives of VA.